3-(5-nitro-2-furyl)-5, 6-dihydroimidazo-[2, 1-b]thiazole and acid addition salts thereof



United States Patent 3,169,970 3-(5 NITRO 2 FURYL) 5,6 DIHYDROIMIDAZO- [2,1-b]THIAZOLE AND ACID ADDITION SALTS THEREOF Harry R. Snyder, Jr., Norwich, N.Y., assignor to The Norwich Pharmacal Company, a corporation of New York No Drawing. Filed Jan. 31, 1963, Ser. No. 255,227

4 Claims. (Cl. IMO-306.8)

H on, 0.... amed...

Its mineral acid salts may be represented by the formula:

wherein X is a chloro or brcmo atom. These compounds are crystalline solids and the salts are readily soluble in water. They have been found to be useful as parasiticides. They are particularly distinguished by their antibacterial and antifungal action and are adapted to be employed as a toxic constituent of compositions designed to prevent and eradicate the growth of fungi and bacteria.

In contrast to past nitrofurans, the compound of this invention and its salts possess a surprisingly greater spectrum of antibacterial activity extending to bacteria such as Psudomonas which have heretofore oftentimes proved to be recalcitrant and resistant to the action of these agents. This behavior is manifested by either the compound or its salts as shown in the table herebelow which is representative of the broad scope of activity against organisms recognized as being causative agents in many animal diseases.

Minimum Inhibitory Concentration in mg. Percent Bacterial Species I 1 II 2 III 3 Staphylococcus aureus 0.625 0.625 0. 625 Escherichia coli 0. 075 0. 075 0. 075 Pseudomonas aerug 2. 5 2. 5 2. 5 Proteus oulqarzs 2. 5 l. 25 2. 5 Salmonella typhosa 0. 075 0. 075 0. 075 Streptococcus pyoqenes-.- O. 625 0.31 0. (S25 Streptococcus aqolactiaa. 2. 5 2. 5 2. 5 Erysipelothriz rhusiopathl 0. 0. 15 0. 15 Aerobacter aeroge'nes 0. 31 0. 31. 0.31

The notation means less than.

I=3-(5-nitro-2-h1ryl)-6, 7-dihydro-5H-imidazo [2, Lb] thiazolium bromide form of unguents, suspensions, dusts, solutions and the like for the prevention and treatment of skin infections. A preferred embodiment in this respect is a composition comprising a mixture of liquid and solid polyethylene glycols as the vehicle, about 0.23% by weight thereof of 3 (S-nitro-Z-furyl)-6,7-dihydro-5H-imidazo[2,1-b]thiazolium chloride and, advantageously, a small amount of hydrochloric acid of the order of about 0.106% by weight of the vehicle as a stabilizing agent. The application of such a composition to the abraded skin of rabbits elicits no adverse response.

The compound of thisinvention and its salts are readily prepared. It is presently preferred to initially prepare a salt such as the bromide by bringing together bromomethyl 5-nitro-2-furyl ketone and ethylene thiourea in the presence of a solvent such as ethanol. To hasten the reaction heat may be supplied to the reaction mixture. When the reaction is completed the desired product, 3-(5- nitro Z-furyl)-6,7-dihydro-5H-imidazo[2,l-b]thiazolium bromide, is recovered in conventional fashion as by cooling the mixture and filtering. If it is desired, the product may be recrystallized from a suitable solvent such as methanol. The salt is readily transformed to the base by dissolving it in water and neutralizing the aqueous solution by the addition of a base. A mild base, such as sodium carbonate, serves to effectively accomplish this purpose. The base, 3-(5-nitro-2-furyl)-5,6-dihydroimidazo- [2,1-b]-thiazole, may be readily converted to a salt. For instance, a solution of it in methanol when treated with concentrated hydrochloric acid produces the chloride salt.

In order that this invention may be readily available to and understood by those skilled in the art, the following illustrative but not limitative examples are appended.

EXAMPLE I 3-(5-n itra-2-furyl)-6,7-dihydro-5H-imidaz0[2,1-b1thiazolium bromide 'ized with aqueous sodium carbonate (pl-1:75).

Calc. for CQHsBIN OgS 33. 97 2. 53 25. 12 Found 34. 33 2. 58 24. 71

EXAMPLE II 3- (5 -ni tro-2-furyl -5 ,6-dihydroimidaz0 [2,] -b] th iazoie 3-(5-nitro-2-furyl)-6,7-dihydro-5H-imidazo[2,1-b]thiazolium bromide (184 g., 0.58 mole) is dissolved in approximately 20.1 of water. The solution is stirred and neutral- The mixture is filtered. The product is washed with water and dried at 65 C. It may be crystallized from benzenehexane mixture.

C H N Calc. for o9H1N3oas 45.56 2.98 17. 71 Found 45. 3. 02 17. 37

EXAMPLE III olium chloride 3 (5-nitro-2-furyl) -S,6,-dihydroimidazo [2, l-b] thiazole (80 g., 0.336 mole) is placed in a flask together with a large volume of methanol. The mixture is heated slightly to aid solution. The solution is acidified with cone. hydrochloric acid (pHca. 2) and filtered While Warm. The solution is then cooled and filtered. The product is washed with ether and dried at 65 C. The yield is 73 g. (79.5%), MP. dec. 250 C. It may be recrystallized from methanol.

I 0 i H i 01 Calc. for C9H3C1N363S 39.49 2.94 12. 96 Found 39. 52 3 06 13. 34

What is claimed is:

1. A member of the group consisting of a compound of the formula:

and a mineral acid salt thereof.

References Cited in the file of this patent UNITED STATES PATENTS 2,354,940 Carter et a1. Aug. 1, 1944 2,485,330 Stewart et a1. Oct. 18, 1949 2,780,629 Kauer Feb. 5, 1957 3,055,910 Dickson et al Sept. 25, 1962 OTHER REFERENCES Fefer et al.: J. Org. Chem, vol. 26, pages 828 835 (1961).

Burger: Medicinal Chemistry (New York, 1960), pages 79-81, and 1135.

Richters Organic Chemistry (New York, 1947), pages 14-15. 

1. A MEMBER OF THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA: 